Lipoproteins are globular, micelle-like particles that consist of a non-polar core of acylglycerols and cholesteryl esters surrounded by an amphiphilic coating of protein, phospholipid and cholesterol. Lipoproteins have been classified into five broad categories on the basis of their functional and physical properties: chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL), and high density lipoproteins (HDL). Chylomicrons transport dietary lipids from intestine to tissues. VLDLs, IDLs and LDLs all transport triacylglycerols and cholesterol from the liver to tissues. HDLs transport endogenous cholesterol from tissues to the liver
Apolipoprotein C-III (also called APOC3, APOC-III, ApoCIII, and APO C-III) is a constituent of HDL and of triglyceride (TG)-rich lipoproteins. Elevated ApoCIII is associated with elevated TG levels and diseases such as cardiovascular disease, metabolic syndrome, obesity and diabetes (Chan et al., Int J Clin Pract, 2008, 62:799-809; Onat et at., Atherosclerosis, 2003, 168:81-89; Mendivil et al., Circulation, 2011, 124:2065-2072; Mauger et al., J. Lipid Res, 2006. 47: 1212-1218; Chan et al., Clin. Chem, 2002. 278-283; Ooi et al., Clin. Sci, 2008. 114: 611-624; Davidsson et al., J. Lipid Res. 2005. 46: 1999-2006; Sacks et al., Circulation, 2000. 102: 1886-1892; Lee et al., Arterioscler Thromb Vasc Biol, 2003. 23: 853-858). ApoCIII slows clearance of TG-rich lipoproteins by inhibiting lipolysis, both through inhibition of lipoprotein lipase (LPL) and by interfering with lipoprotein binding to cell-surface glycosaminoglycan matrix (Shachter, Curr. Opin. Lipidol, 2001, 12, 297-304). As ApoCIII inhibits LPL leading to a decrease in lipolysis of TGs, it would be unexpected that inhibition of ApoCIII would have a beneficial effect in LPL deficient (LPLD) subjects.
LPLD is characterized by the inability of affected individuals to produce functionally active LPL. LPL is mainly produced in skeletal muscle, fat tissue, and heart muscle and has multiple key functions, among which is the catabolism of TG-rich lipoproteins (e.g. VLDL) and chylomicrons (CM). Off-loading TG from CM (and VLDL) normally protects against excessive postprandial rise in CM mass and TG. In LPLD, LPL is dysfunctional and more than 12 hours after meals hyperTG and chylomicronaemia are still present and visible as lipemia.
The Fredrickson system is used to classify primary (genetic) causes of dyslipidemia such as hypertriglyceridemia in patients. Fredrickson Type I (also known as LPLD or Familial Chylomicronemia Syndrome (FCS)) is usually caused by mutations of either the LPL gene, or of the gene's cofactor ApoC-II, resulting in the inability of affected individuals to produce functionally active LPL (i.e. LPLD). Patients have mutations that are either homozygous (having the same mutation on each allele) or compound heterozygous (having different mutations on each allele). The prevalence is approximately 1 in 1,000,000 in the general population and much higher in South Africa and Eastern Quebec as a result of a founder effect.
Currently, Fredrickson Type I, FCS, LPLD, patients respond minimally, or not at all, to TG-lowering drugs such as statins, fibrates and nicotinic acid (Tremblay et al., J Clin Lipidol, 2011, 5:37-44; Brisson et al., Pharmacogenet Genom, 2010, 20:742-747). Clinical management of Fredrickson Type I, FCS, LPLD, patients generally consist of severe reduction in all dietary fat to much less than 20% of caloric intake and the use of medium-chain TG, which are absorbed via the portal system and therefore do not directly enter into plasma. Such a life-long dietary regimen presents significant compliance issues for patients. Even when patients are compliant to the diet and are tightly followed in a lipid clinic by a dietician and a medical team, TGs often do not decrease below the threshold of increased pancreatitis risk. Recently, a gene therapy product (Glybera®) has been approved in Europe for treating adult LPLD patients suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. Patients treated with Glybera® require administration of an immunosuppressive drug prior to and following Glybera® treatment. Glybera® will only be offered through dedicated centers with expertise in treating LPLD and by specially trained doctors to ensure ongoing safety of the treatment (http://www.uniqure.com/products/glybera/).
Accordingly, there is still a need to provide patients with Fredrickson Type I dyslipidemia, FCS, LPLD, novel treatment options. Antisense technology is emerging as an effective means for reducing the expression of certain gene products and may prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of ApoCIII. We have previously disclosed compositions and method for inhibiting ApoCIII by antisense compounds in US 20040208856 (U.S. Pat. No. 7,598,227), US 20060264395 (U.S. Pat. No. 7,750,141), WO 2004/093783 and WO 2012/149495, all incorporated-by-reference herein. An antisense oligonucleotide targeting ApoCIII has been tested in a Phase I clinical trial and was shown to be safe. Currently, an antisense oligonucleotide targeting ApoCIII is in Phase II clinical trials to assess its effectiveness in the treatment of diabetes or hypertriglyceridemia.